One of the major obstacles that impede the wide application of therapeutic protein products is their potential immunological responses, especially for those obtained from non-human sources. These responses decrease the efficacy of the protein and cause adverse events such as anaphylaxis, cytokine-release syndrome, and cross-reactive neutralization of endogenous proteins, all which may threaten patient safety. Currently, the most successful strategy to mitigate immune response to foreign proteins is the surface conjugation of the amphiphilic polymer polyethylene glycol (PEG) to cover the protein surface epitopes in the PEGylation process. This surface coverage strategy has been shown to decrease to some extent immune responses to the underlying protein and more than ten PEGylated protein products have been approved by the Food and Drug Administration (FDA). However, recent studies have demonstrated the repeated administration of PEGylated therapeutics generating anti-PEG antibodies both in animal models and clinical trials, which directly challenges the future of the PEGylation technology. One typical example is the PEGylated version of the highly immunogenic mammalian uricase for the therapy of gout (approved by FDA in 2010), where the high rate of anti-PEG generation after administration has caused extensive attention. We believe there are two shortcomings for the current PEGylation technology: 1) the PEG polymer is immunogenic and 2) PEG forms sparse brush structures that provides inadequate surface coverage due to its existing and available chemistries. Thus, we propose here a poly(carboxybetaine) (pCB) based nanogel encapsulation technique to overcome these problems simultaneously. In prior studies, we have demonstrated that pCB is a biocompatible material with better non-fouling property and less immunogenicity than PEG. Using pCB as a shielding material, the resulting nanogel will provide 100% protein surface coverage. This new approach adopts the same principle as PEGylation in that coverage of surface epitopes can diminish protein immune responses, but utilizes a non-immunogenic base material and provides a more comprehensive surface coverage. Thus, we hypothesize that pCB-coated uricase will have better circulation profiles and less immunogenicity compared to the current PEGylated version. This hypothesis will be addressed in the experiments of the following Specific Aims: 1) Development of uricase-loaded pCB nanogels with high activity; 2) determination of nanogel stability, stealth characteristics and protease resistance; and 3) determination of circulation profiles, biodistribution, and antibody responses. Successful completion of this proposal will culminate in a new approach for the entire protein pharmaceutical field to generate alternatives to the existing, but insufficient PEGylation technology, producing safer and more effective protein therapeutics.